Identifying cellular and molecular signatures from distinct T cell receptor clonotypes associated with favorable immune checkpoint inhibitor responses in HNSCCs

识别与 HNSCC 中有利的免疫检查点抑制剂反应相关的不同 T 细胞受体克隆型的细胞和分子特征

• 批准号: 10573334
• 负责人: Robert L. Ferris
• 金额: $ 68.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573334
• 关键词: Adjuvant Study; Aftercare; Antibodies; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Prognosis; Carcinogens; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Clinical Trials; Clonal Expansion; Combination immunotherapy; Coupled; Data; Disease; Future; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Immune checkpoint inhibitor; Institution; Link; Modeling; Molecular Profiling; Mus; Neoadjuvant Therapy; Nivolumab; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Phenotype; Population; Publishing; Resectable; Sampling; Splenocyte; Surrogate Markers; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Tumor Antigens; Tumor Expansion; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Validation; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD-L1 therapy; antigen-specific T cells; cancer immunotherapy; cancer type; checkpoint therapy; improved; insight; minimally invasive; molecular marker; mouse model; novel; programmed cell death protein 1; response; single-cell RNA sequencing; transcriptome; transcriptomics; tumor

Project Summary/Abstract Cancer immunotherapy has become one of the pillar therapies in treating cancer patients, exemplified by immune checkpoint inhibitors (ICI) (e.g., anti-PD1). While ICIs have significantly improved the prognosis of cancer patients, the response rate to ICI monotherapy remains low (10-20%) for many types of cancer, such as head and neck squamous cell carcinoma (HNSCC). Some variability may be explained by human papillomavirus (HPV)- vs. carcinogen-induced, tumor antigen-specific T cell responses in HPV+ or HPV− HNSCC, reflecting a unique disease opportunity to investigate ICI responsiveness. Thus, it is vital to better understand the mechanisms underlying heterogenous responses to ICI and to identify new targets that may sensitize HNSCCs to mono- and combination immunotherapy. In this application, we propose to focus on T cell phenotypes associated with clinical response, dynamic changes in specific T cell receptor (TCR) clonotypes, and TCR clonotype-specific transcriptomic changes in response to ICI treatment, using HNSCC patient samples from an ongoing clinical trial at our institution and detailed studies using murine HNSCC models. Using HCC 18-139 trial samples, we will compare tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) from pre- and post-treatment samples and examine TCR dynamics and T cell phenotypes in blood (minimally invasive and readily accessible) and in tumors in the context of ICI-induced anti-tumor immunity. Our mouse model allows functional validation among distinct TCR clonotypes correlating with ICI responses, and permits manipulation of novel potential targets to enhance clinical responsiveness as well as lay the groundwork for future clinical trials. Our proposed studies will identify cellular and molecular markers to better predict ICI responses in HNSCC patients treated with different combinations of ICIs and would facilitate finding novel mechanisms of differential ICI responses using transcriptomic differences in distinct clonal TCR-bearing T cell populations. A unique strength of our proposal is integration of human clinical trial samples and mouse models as a more powerful platform to uncover mechanistic insights that are translatable into the clinical setting.

项目总结/摘要 癌症免疫疗法已成为治疗癌症患者的支柱疗法之一， 免疫检查点抑制剂（ICI）（例如，抗PD 1）。虽然ICIs显著改善了 在癌症患者中，对于许多类型的癌症，ICI单一疗法的应答率仍然很低（10-20%），例如 头颈部鳞状细胞癌。一些变异可能是由人乳头瘤病毒 HPV+或HPV− HNSCC中HPV-与致癌物诱导的肿瘤抗原特异性T细胞应答，反映了 研究ICI反应性的独特疾病机会。因此，更好地了解 对ICI的异质性反应的潜在机制，并确定可能使HNSCCs敏感的新靶点 单一和联合免疫疗法。在本申请中，我们建议关注T细胞表型 与临床反应、特异性T细胞受体（TCR）克隆型的动态变化和TCR 使用来自一个研究对象的HNSCC患者样本， 我们机构正在进行的临床试验和使用鼠HNSCC模型的详细研究。使用HCC 18-139试验 样本，我们将比较肿瘤浸润淋巴细胞（TIL）和外周血淋巴细胞（PBL），从前 和治疗后样品，并检查血液中的TCR动力学和T细胞表型（微创和 容易获得）和在ICI诱导的抗肿瘤免疫的背景下在肿瘤中。我们的小鼠模型 在与ICI反应相关的不同TCR克隆型之间进行功能验证，并允许操纵 新的潜在靶点，以提高临床反应性，并为未来的临床试验奠定基础。 我们提出的研究将确定细胞和分子标志物，以更好地预测HNSCC的ICI反应 患者接受不同的ICI组合治疗，将有助于发现新的差异机制， 使用不同克隆TCR携带T细胞群体中的转录组差异的ICI应答。一个独特 我们的建议的优势是整合人类临床试验样品和小鼠模型，作为一个更强大的 平台，以揭示可转化为临床环境的机械见解。